Hadfield, John - University of Salford - Biomedical Research Centre

个人简介

I am a Senior Lecturer in Medicinal Chemistry at the University of Salford. I studied for a BSc in Chemistry at the University of Nottingham 1976-9. I was awarded a PhD in Organic Chemistry from Trent Polytechnic in 1984. I was a Postdoctoral research fellow in the department of chemistry at the University of Warwick 1984-86. I was a Research fellow/Team Leader at the Paterson Institute for Cancer Research, Christie Hospital, Manchester 1987-2001. I was appointed as a Lecturer in Medicinal Chemistry at the University of Salford in 2001, and Senior Lecturer in 2008.

研究领域

The over-proliferation of vasculature contributes to the onset and continuation of several diseases which include cancer, psoriasis, endometriosis and ocular disorders (diabetic retinopathy, macular degeneration). My research aims to develop several types of low molecular weight agents which have shown promise as vascular targeting agents. The primary target for these agents is the dimeric protein tubulin and the interaction of these agents with tubulin leads to the rapid destruction of over-proliferating vasculature. The destruction of over-proliferating vasculature in the eye will have implications for the treatment of macular degeneration and diabetic retinopathy. As over-proliferation of vasculature is also responsible for endometriosis this condition should also be treatable with antivascular agents. Also the neovasculature which supplies blood and nutrients to solid tumours is targeted by antivascular agents. For both ocular diseases, endometriosis and cancer, targeting the vasculature has several potential benefits over conventional treatments: Antivascular agents act primarily on rapidly proliferating vasculature and act on the vascular endothelial cells causing the cells to round up and block the blood vessel. The agents also tend to have a short pharmacokinetic half-life and the endothelial cells are exposed to the highest concentration of drug in circulation. Rapid clearance of the drug reduces the potential of the drug to penetrate other tissues and this leads to reduced side effects. The cells that make up the blood vessels are not themselves malignant and are therefore unlikely to undergo genetic changes that give rise to resistance to direct acting anti-tumour agents. Vascular targeting therapy should be applicable to all solid tumours and vascular targeting agents can destroy tumours which conventional drugs can penetrate only poorly. We have developed several agents based on the combretastatin, chalcone and benzothiophene pharmacophore. Some of the agents have shown antivascular effects with potencies as good as or better than combretastatin A-4 (an agent which is presently in Phase 2 clinical trials.) We have also developed a novel stereoselective two-step synthesis of combretastatin A-4. These findings have been patented. My group has also discovered a novel pharmacophore which shows potent antivascular properties. This finding is presently being evaluated and has been patent protected. Complementary to the research into antivascular agents we are researching the potential of two-photon activation of combretastatins. This activation will isomerise non-toxic trans combretastatins to their biologically active cis isomers using visible light. A range of kinase inhibitors are also being developed: the ability to modulate the activity of selected kinases may form the basis of a novel strategy for cancer chemo-prevention. These findings have been patented. Onco-NX is developing a quinone pro-pro drug which requires two different types of enzyme to create the biologically active species.

近期论文

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L. Hampson L, X. T. He, A. W. Oliver, J. A. Hadfield, T. Kemp, J. Butler, A. McGown, H. C. Kitchener and I. N. Hampson. Analogues of Y27632 increase gap junction communication and suppress the formation of transformed NIH3T3 colonies. Br. J. Cancer, 2009, 101, 829-839. D. J. Edwards, J. A. Hadfield, T. W. Wallace and S. Ducki. Tubulin-binding Dibenz[c,e]oxepines as Colchinol Analogues for Targeting Tumour Vasculature. Org. Biomol. Chem., 2011, 219-31. J. A. Hadfield, N. Hirst, K. Gaukroger, N. J. Lawrence and A. T. McGown. A Practical Radiosynthesis of a Tritium-Labelled Fluoro Combretastatin. J. Labelled Compounds and Radiopharmaceuticals, 2012, 55, 303-6. P. H. Jalily, J. A. Hadfield, N. Hirst and S. B. Rossington. Novel Cyanocombretastatins as Potent Tubulin Polymerisation Inhibitors. Bioorg. Med. Chem. Lett., 2012, 22, 6731-4. R. H. Bisby, S. W. Botchway, J. A. Hadfield, A. T. McGown, A. W. Parker and K. M Scherer. Fluorescence Lifetime Imaging of E Combretastatin Uptake and Distribution in Mammalian Cells. Eur. J. Cancer., 2012, 48, 1896- 903. R. H. Bisby, S. W. Botchway, G. M. Greetham, J. A. Hadfield, A. T. McGown, A. W. Parker, K. M Scherer and M. Towrie. Time-resolved Nanosecond Fluorescence Lifetime Imaging and Picosecond Infrared Spectroscopy of Combretastatin A-4 in Solution and in Cellular Systems. Measurement Science and Technology, 2012, 23, 084001.